International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Shanghai, China; The Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
Gastroenterology. 2013 Dec;145(6):1436-48.e1-12. doi: 10.1053/j.gastro.2013.08.009. Epub 2013 Aug 9.
BACKGROUND & AIMS: Aberrant expression of MUC15 correlates with development of colorectal adenocarcinoma, and MUC15 has been reported to prevent trophoblast invasion of human placenta. However, little is known about the role of MUC15 in pathogenesis of hepatocellular carcinoma (HCC).
We analyzed HCC samples and matched nontumor liver tissues (controls) collected from 313 patients who underwent hepatectomy in Shanghai, China, from January 2006 through September 2009. Levels of messenger RNAs and proteins were determined by immunohistochemical, quantitative reverse transcription polymerase chain reaction, and immunoblot analyses. Statistical analyses were used to associate levels of MUC15 with tumor features and patient outcomes.
Levels of MUC15 messenger RNA and protein were reduced in a greater percentage of HCC samples than control tissues. Tumors with reduced levels of MUC15 were more likely to have aggressive characteristics (eg, high levels of α-fetoprotein, vascular invasion, lack of encapsulation, and poor differentiation) than those with low levels. Patients whose tumors had reduced levels of MUC15 had shorter overall survival times (24 months vs 46 months for patients with tumors with high levels of MUC15) and time to disease recurrence. Stable expression of MUC15 in HCC cell lines (SMMC-7721 and HCC-LM3) reduced their proliferation and invasive features in vitro, and ability to form metastatic tumors in mice. MUC15 reduced transcription of the matrix metalloproteinases 2 and 7 increased expression of tissue inhibitor of metalloproteinase-2, which required phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. Physical interaction between MUC15 and epidermal growth factor receptor led to its relocation and degradation within early endosomes and was required for inactivation of phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling.
Reduced levels of MUC15 in HCCs are associated with shorter survival times of patients and reduced time to disease recurrence. Expression of MUC15 in HCC cells reduces their aggressive behavior in vitro and in mice by inducing dimerization of epidermal growth factor receptor and decreasing phosphoinositide 3-kinase signaling via v-akt murine thymoma viral oncogene homolog.
MUC15 的异常表达与结直肠腺癌的发生发展相关，已有研究报道 MUC15 可阻止人胎盘滋养层的侵袭。然而，MUC15 在肝细胞癌（HCC）发病机制中的作用仍知之甚少。
我们分析了 2006 年 1 月至 2009 年 9 月在中国上海行肝切除术的 313 例患者的 HCC 样本和匹配的非肿瘤肝组织（对照）。通过免疫组化、实时定量逆转录聚合酶链反应和免疫印迹分析来检测信使 RNA 和蛋白水平。统计学分析用于将 MUC15 水平与肿瘤特征和患者预后相关联。
与对照组织相比，MUC15 信使 RNA 和蛋白在更大比例的 HCC 样本中表达降低。与低水平 MUC15 相比，MUC15 水平降低的肿瘤更有可能具有侵袭性特征（例如，高水平的甲胎蛋白、血管侵袭、缺乏包膜和低分化）。MUC15 水平降低的肿瘤患者的总生存时间（24 个月 vs 高 MUC15 水平肿瘤患者的 46 个月）和疾病复发时间更短。在 HCC 细胞系（SMMC-7721 和 HCC-LM3）中稳定表达 MUC15，可降低其体外增殖和侵袭特性，并降低在小鼠中形成转移性肿瘤的能力。MUC15 降低了基质金属蛋白酶 2 和 7 的转录，增加了组织金属蛋白酶抑制剂 2 的表达，这需要磷酸肌醇 3-激酶-v-akt 鼠胸腺瘤病毒癌基因同源物信号。MUC15 与表皮生长因子受体的物理相互作用导致其在早期内体中的重定位和降解，这是磷酸肌醇 3-激酶-v-akt 鼠胸腺瘤病毒癌基因同源物信号失活所必需的。
HCC 中 MUC15 水平降低与患者生存时间缩短和疾病复发时间缩短相关。在 HCC 细胞中表达 MUC15 通过诱导表皮生长因子受体二聚化并通过 v-akt 鼠胸腺瘤病毒癌基因同源物降低磷酸肌醇 3-激酶信号，降低其体外和小鼠中的侵袭行为。
